Study of AZD3632 Monotherapy or in Combination With Anticancer Agents in Participants With Advanced Haematologic Malignancies With KMT2Ar, NPM1m, or Other Genotypes Associated With HOX Overexpression
- Conditions
- Acute Lymphoblastic LeukaemiaHigher-risk Myelodysplastic SyndromesAcute Myeloid Leukaemia
- Interventions
- Drug: AZD3632
- Registration Number
- NCT07155226
- Lead Sponsor
- AstraZeneca
- Brief Summary
The purpose of this study is to understand the safety, tolerability, efficacy, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of orally administered AZD3632 in participants with advanced haematologic malignancies with KMT2Ar, NPM1m, or other genotypes associated with homeobox (HOX) overexpression.
- Detailed Description
This is a first in human (FTiH), open-label, multi-centre study of AZD3632 in participants with relapsed or refractory acute leukaemia or myelodysplastic Syndromes (MDS) with HOX overexpression genotypes.
This study includes multiple modules (module 1 and module 2) each investigating AZD3632 in a specific population and/or in combination with other anticancer agents.
Module 1 is a dose escalation of AZD3632 monotherapy. Module 2 will investigate the safety, PK, and tolerability when co-administered with posaconazole.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 84
Core criteria:
- Adequate organ function.
- Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Module 1:
- Advanced haematologic malignancy - a) for dose escalation - diagnosis of acute leukemia or myelodysplastic neoplasia (MDS) and harbouring one of the genetic alterations per local testing associated with upregulation of HOX; b) for Backfill - diagnosis of harbouring a KMT2Ar or NPM1m per local testing.
- Participants must have relapsed/refractory (R/R) and measurable disease: a) Relapsed and refractory (R/R) acute leukaemia after standard of care therapy including but not limited to 1 to 2 cycles of intensive chemotherapy or venetoclax combinations; b) R/R MDS is defined by ≥ 5% blasts in the bone marrow and/or persistence of peripheral blasts after treatment with at least an HMA. Participants ineligible for the treatment with an HMA and without any other standard of care (SoC) options are allowed to enrol; c) White blood cell count below 25,000/μL. Participants may receive cytoreduction per protocol-specified criteria; d) Performance status: Eastern Cooperative Operative Group (ECOG) ≤ 2; e) Life expectancy: ≥ 8 weeks.
Module 2:
- Participants must have relapsed/refractory and measurable disease: a) R/R acute leukaemia after standard of care therapy including but not limited to 1 to 2 cycles of intensive chemotherapy or venetoclax combinations; b) R/R MDS is defined by ≥ 5% blasts in the bone marrow and/or persistence of peripheral blasts after treatment with at least an HMA. Participants ineligible for the treatment with an HMA and without any other SoC options are allowed to enrol; c) White blood cell count below 25,000/μL. Participants may receive cytoreduction per protocol-specified criteria; d) Performance status: ECOG ≤ 2; e) Life expectancy: ≥ 8 weeks.
Key
Core criteria:
- Participants with Burkitt lymphoma/leukaemia or Acute Promyelocytic Leukaemia.
- Active testicular or active central nervous system (CNS) (> CNS1 or radiographic) involvement by leukaemia.
- Unresolved treatment-related toxicities Grade ≥ 2 from prior therapy.
- Abnormal levels of potassium or magnesium prior to first dose of AZD3632.
Module 1:
- Receipt of non-CNS radiation therapy within 2 weeks and of CNS radiation within 8 weeks of the first scheduled dose.
- Receipt of any investigational or non-investigational anticancer agents, including non-biologic agents, biologic agents and/or prior treatment other menin inhibitors (backfill participants only).
- For nested food effect participants - diagnosis of diabetes mellitus (Type I or Type II).
Module 2:
- Receipt of any non-investigational anticancer agents, including non-biologic agents and/or biologic agents or receipt of non-CNS or CNS radiation therapy.
- Participants for whom treatment with posaconazole is contraindicated per the local prescribing information.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Module 1: AZD3632 dose 1 AZD3632 Participants will receive AZD3632 (dose 1) through the treatment period. Module 1: AZD3632 dose 3 AZD3632 Participants will receive AZD3632 (dose 3) through the treatment period. Module 1: AZD3632 dose 6 AZD3632 Participants will receive AZD3632 (dose 6) through the treatment period. Module 1: AZD3632 dose 2 AZD3632 Participants will receive AZD3632 (dose 2) through the treatment period. Module 1: AZD3632 dose 4 AZD3632 Participants will receive AZD3632 (dose 4) through the treatment period. Module 2: AZD3632 + posaconazole Posaconazole Participants will receive AZD3632 alone, then will receive AZD3632 in combination with posaconazole through treatment period. Module 1: AZD3632 dose 5 AZD3632 Participants will receive AZD3632 (dose 5) through the treatment period. Module 2: AZD3632 + posaconazole AZD3632 Participants will receive AZD3632 alone, then will receive AZD3632 in combination with posaconazole through treatment period.
- Primary Outcome Measures
Name Time Method Module 1: Number of participants with dose-limiting toxicity (DLT) At the end of Cycle 1 (each cycle is 28 days) Safety and tolerability of AZD3632 monotherapy in participants with advanced haematologic malignancies will be assessed.
Module 1 and Module 2: Number of participants with dose modification, delay and discontinuations due to adverse events (AEs) Up to 3 year 10 months Safety and tolerability of AZD3632 monotherapy in participants with advanced haematologic malignancies will be assessed.
Module 1 and Module 2: Number of participants with treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs) and serious adverse vents (SAEs) Up to 3 year 10 months Safety and tolerability of AZD3632 monotherapy in participants with advanced haematologic malignancies will be assessed. Adverse events will be defined as treatment-emergent if they have an onset or worsen (by investigator report of a change in intensity) during the study treatment or the safety follow-up period but prior to any subsequent cancer therapy.
- Secondary Outcome Measures
Name Time Method Module 1 and Module 2: Maximum concentration (Cmax) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy (module 1) and in combination with posaconazole (module 2) will be assessed.
Module 1: Trough concentration (Ctrough) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy will be assessed.
Module 1: Apparent volume of distribution based on the terminal phase (VZ/F) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy will be assessed.
Module 1 and Module 2: Time of maximum concentration (Tmax) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy (module 1) and in combination with posaconazole (module 2) will be assessed.
Module 1: Area under the plasma concentration-time Curve from Time Zero to Infinity (AUC[inf]) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy will be assessed.
Module 1 and Module 2: Area under the curve from time 0 to the time of last measurable concentration (AUC[0-t]) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy (module 1) and in combination with posaconazole (module 2) will be assessed.
Module 1: Area under concentration-time curve in the dosing interval (AUCtau) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy will be assessed.
Module 1: Half-life (t1/2) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy will be assessed.
Module 1: Apparent total body clearance (CL/F) of AZD3632 From Day 1 to 3 year 10 months The PK of AZD3632 as monotherapy will be assessed.
Module 1: Maximum concentration (Cmax) of AZD3632 (food effect) From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 1: Time of maximum concentration (Tmax) of AZD3632 (food effect) From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 1 and Module 2: Area under the curve from time 0 to the time of last measurable concentration (AUC[0-t]) of AZD3632 (food effect) From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 1: Area under concentration-time curve in the dosing interval (AUCtau) of AZD3632 (food effect) From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 1: Minimum concentration (Cmin) of AZD3632 (food effect) From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 1: Ratio of Cmax between fed and fasted state From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 1: Ratio of AUC(0-t) between fed and fasted state From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 1: Ratio of AUCtau between fed and fasted state From Day 1 to 3 year 10 months The preliminary effect of food on plasma PK of AZD3632 (conducted in a nested evaluation during backfills) will be assessed.
Module 2: Plasma geometric mean ratio of Cmax From Day 1 to 3 year 10 months The PK pf AZD3632 when co-administered with posaconazole will be assessed.
Module 1 and Module 2: Duration of response (DoR) Up to 3 year 10 months DoR in participants with acute leukaemia is defined as the time from date of first documented complete response (CR/CRh) until date of first documented relapse or death (by any cause in the absence of relapse) as assessed by investigator at local site.
DoR in participants with MDS is defined as the time from date of first documented objective response CR (or CR equivalent), CRL, CRh, PR, or HI until date of first documented relapse or death (by any cause in the absence of relapse) as assessed by investigator at local site.Module 2: Plasma geometric mean ratio of AUC From Day 1 to 3 year 10 months The PK pf AZD3632 when co-administered with posaconazole will be assessed.
Module 2: Plasma concentration of posaconazole From Day 1 to 3 year 10 months The PK pf AZD3632 when co-administered with posaconazole will be assessed.
Module 1 and Module 2: Complete response rate (CR + CRh) Up to 3 year 10 months Complete response rate is defined as the percentage of participants who have a complete remission (CR) or complete remission with partial haematological recovery (CRh) as assessed by the investigator at local site.
Module 1 and Module 2: Time to response (TTR) Up to 3 year 10 months TTR in participants with acute leukaemia is defined as the time from date of first dose until date of first documented complete response (CR/CRh) among participants with acute leukaemia in the Response Evaluable Set who achieved complete response as assessed by investigator at local site.
TTR in participants with MDS is defined as the time from date of first dose until date of first documented objective response a CR (or CR equivalent), complete response with limited count recovery \[CRL\], CRh, partial response \[PR\], or haematologic improvement \[HI\]) among participants with MDS in the Response Evaluable Set who achieved objective response as assessed by investigator at local site.Module 1 and Module 2: Transfusion Independence (TI) Up to 3 year 10 months TI is defined as no RBC and no platelet transfusion during any consecutive period of at least 56 days post-baseline after starting treatment with AZD3632 or cessation of treatment with AZD3632 but prior to start of subsequent new therapy.
Module 1 and Module 2: Event-free Survival (EFS) Up to 3 year 10 months EFS for participants with acute leukaemia is defined as the time from date of first dose until date of relapse, progressive disease, failure to achieve at least Morphologic leukaemia-free state (MLFS) by end of Cycle 6, or death due to any cause as assessed by investigator at a local site.
EFS for participants with MDS is defined as the time from date of first dose until date of relapse, progressive disease, failure to achieve at least HI by end of Cycle 6, or death due to any cause.Module 1 and Module 2: Overall Survival (OS) Up to 3 year 10 months OS is defined as the time from date of first dose until date of death due to any cause regardless of whether the participant withdraws from study therapy or receives another anticancer therapy.
Module 1 and Module 2: Percentage of participants who receive subsequent allogeneic hematopoietic stem cell transplant (HSCT) Up to 3 year 10 months Percentage of participants with acute leukaemia and MDS who receive subsequent allogeneic HSCT will be reported.
Module 1 and Module 2: Overall Response Rate (ORR) Up to 3 year 10 months ORR in participants with myelodysplastic syndromes (MDS) is defined as the percentage of participants who have a CR (or CR equivalent), CRL, CRh, PR, or HI as determined by investigator at a local site.
Module 1 and Module 2: Time to Progression to acute myeloid leukaemia (AML) Up to 3 year 10 months Time to progression to AML is defined from the time of first dose of AZD3632 until first diagnosis of AML, regardless of discontinuation of treatment or receiving of subsequent therapy.
Trial Locations
- Locations (1)
Research Site
🇬🇧Edinburgh, United Kingdom
Research Site🇬🇧Edinburgh, United Kingdom